As a part of our on-going research focusing on therapeutic strategies against HIV transmission and disease progression, the long-term goal of this program is to develop novel therapeutic strategies against HIV replication in lymphoid tissues. While the tissues that harbor residual HIV outside the lymphatic system remains elusive, it is clear that a low but detectable fraction of HIV is found in visceral (e.g., mesenteric) lymph nodes, even in the presence of highly active anti-retroviral (combination drug) therapies (HAARTs). Our recent analysis of HIV protease inhibitor levels in tissues (i.e., lymph nodes) and blood indicated that drug exposure in lymph nodes is far less than that of systemic (blood) exposure in human subjects under HAARTs. Increasing drug exposure to lymphoid tissues without increasing drug toxicity may further reduce the virus levels and intracellular virus concentrations in these tissues. We will determine whether increasing local drug concentration will further reduce the virus load in the lymphatic system by testing the following hypotheses: Hypothesis 1: Enhanced anti-HIV drug accumulation in lymph nodes throughout the lymphatic system can be achieved using lipid-association. Hypothesis 2: Lipid-mediated enhanced drug accumulation strategy will further reduce the frequency of virus-infected cells or virus concentration in lymphoid tissues. Data collected from this study will provide pharmacologic, therapeutic, and safety information essential for further evaluation of the novel drug strategies to enhance drug availability in lymph nodes and other tissues where virus typically persists.